Thermodynamic studies of substrate binding to native alpha- chymotrypsin and to forms of chymotrypsin in which catalytically essential residues in the enzyme are modified, are proposed. Modified forms of a chymotrypsin that will be studied are anhydroserinyl-195- alpha-chymotrypsin and N-methylhistidinyl-57-alpha-chymotrypsin. It has been shown that substrates bind unproductively to these modified enzymes. Substrates utilized in these binding studies will be of three types: 1) substrate molecules that contain an amide function and bind water more tightly than in 2 below; 2) substrate molecules in which the amide function in 1 above is replaced by an ester function; and 3) substrates that bind well, but are hydrolyzed slowly by the enzyme. The enthalpy and entropy data for binding productively to native enzyme and non-productively to modified enzyme with substrates in groups 1-3, will give information on the mechanisms of substrate distortion and induced fit in enzyme catalysis, the role of catalytic residues of the active site in productive enzyme-substrate complexes, and the effect of substrate desolvation on binding.